Mice injected with sublethal doses murine cytomegalovirus (MCMV) exhibit rapid and dramatic changes in their ability to generate in vitro cytotoxic T lymphocyte responses to hapten-self and to alloantigens, and to produce IL 2 and express IL 2 receptors. Within three days after intraperitoneal injection of MCMV, the CTL responses to hapten-self and alloantigens are abrogated or severely reduced. This is followed by rapid recovery to a normal level of CTL potential. Injection of F1 hybrid mice with either MCMV or parental spleen cells (graft-versus-host reaction - GVHR) resulted in rapid and severe immunosuppression. Inoculation of either the virus or parental cells were selected so that they would be below the threshold for severe immunosuppression. However, when these two inocula were combined, severe immunosuppression was observed. Furthermore, injection of F1 mice with parental lymphocytes that recognize only class I MHC determinants does not result in immune suppression. However, a combination of class I recognition and MCMV infection results in profound immune suppression. Infection of host mice with MCMV prior to induction of GVH resulted in augmented immune suppression, whereas infection of donor mice with MCMV before induction of GVH resulted in reduced immune suppression. The combination of MCMV and GVHR also resulted in interstitial pneumonitis, whereas either insult alone had no detectable pathogenic effect on the lungs. These studies permit the investigation of the immunosuppression of MCMV infection and the possibility consequences of CMV infection coupled with a GVHR.